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Papers In Press, published online ahead of print July 13, 2004
Department of Orthopedic Surgery, Washington University, St. Louis, MO 63110
Corresponding Author: abuamery{at}msnotes.wustl.edu
Activation of the transcription factor NF-
J. Biol. Chem, 10.1074/jbc.C400258200
Submitted on June 3, 2004
Revised on June 29, 2004
Accepted on July 13, 2004
The IKK inhibitor, NEMO-binding domain peptide, blocks osteoclastogenesis and bone erosion in inflammatory arthritis
B leads to expression of ample genes that regulate inflammatory and osteoclastogenic responses and requires induction of IB kinase (IKK) complex that phosphorylates the NF-B inhibitory protein IB and leads to its dissociation form the NF-B complex, thus permitting nuclear translocation of NF-B. The IKK complex contains several factors primarily IKK
, IKK
, and the regulatory kinase IKK
, also known as NEMO. NEMO regulates the IKK complex activity through its binding to carboxyl-terminal region of the IKK and IKK, termed NEMO-binding domain (NBD). In this regard, a cell-permeable NBD peptide has been shown to block association of NEMO with the IKK complex, inhibits cytokine-induced activation of NF-B, and ameliorates inflammatory responses. Given the pivotal role of cytokine-induced NF-B in osteoclastogenesis and inflammatory bone loss, we deduced that cell-permeable TAT-NBD peptide may hinder osteoclastogenesis and bone erosion in inflammatory arthritis. Using NBD peptides, we show that wild type, but not mutant, NBD blocks IKK activation and reduces TNF-induced promoter and DNA-binding activities of NF-B and inhibits cytokine-induced osteoclast formation by osteoclast precursors (OCPs). Consistent with the key role of NF-B in osteolytic and inflammatory responses in vivo, wild type TAT-NBD peptide administered into mice prior to induction of inflammatory arthritis efficiently blocks in vivo osteoclast recruitment, inhibits focal bone erosion, and ameliorates inflammatory responses in the joints of arthritic mice. The mutant NBD peptide fails to execute these functions. These results provide strong evidence that IKKs are potent regulators of cytokine-induced osteoclastogenesis and inflammatory arthritis. More importantly, blockade of NEMO assembly with the IKK complex is a viable strategy to avert inflammatory osteolysis.
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